Hormones are a kind of compounds influencing cell activity in different manners. In many cases, hormones act as messengers to trigger specific cellular reactions and activities. However, many effects induced by hormones are not caused by specific effects of hormones. On the contrary, a hormone firstly combines with a receptor, thereby triggering release of a second compound, and the second compound further influences cellular activity. In this case, the hormone is called as first messenger, and the second compound is called as second messenger. Cyclic adenosine monophosphate (adenosine-3″,5′-cyclic monophosphate, cAMP or cyclic AMP) is considred as a second messenger of hormones such as adrenaline, glucagon, calcitonin, adrenocorticotrophic hormone, lipotropic hormone, luteinizing hormone, norepinephrine, parathormone, thyroid stimulating hormone and pitressin. Thus, cAMP mediates cellular reaction with hormones, and cAMP also mediates cellular reaction with various neurotransmitter.
Phosphodiesterases (PDEs) have function of hydrolyzing second messengers in cells, degrading cAMP in cells, thereby terminating biochemical action transducted by these second messengers. PDEs family has 11 enzymes, in which PDE4 enzyme is a specific cAMP hydrolase, mainly distributing in airway smooth muscle cells as well as inflammatory cells and immune cells such as lymphocytes, macrophages, neutrophile granulocytes, eosinophilic granulocytes, basophilic granulocytes, mononuclear leucocytes, epithelial cells, regulating cAMP level in these cells.
PDE4 inhibitors can inhibit activities of these immune cells and inflammatory cells, can be used for treatment of diseases caused by inflammations, such as asthma, chronic obstructive pulmonary disease (COPD), rheumatoid arthritis, multiple sclerosis, Alzheimer's disease (AD), Parkinson's disease (PD) and stroke which are central nervous system diseases resulting from neuron injury induced by potential inflammation.
Roflumilast is the first marketed PDE4 inhibitor. Patients with COPD showed a significant decrease in number of neutrophile granulocyte in phlegm after more than 4 weeks of oral administration of Roflumilast, and slight improvement in pulmonary function after more than 6-12 months of oral administration. But it could not significantly alleviate acute exacerbation of symptom or improve life quality, which reason might be the side-effects limited the application dose.
Cilomilast is a PDE4 inhibitor, and is terminated for use at phase III due to adverse reaction of emesis. One concerned problem of using PDE4 inhibitor is side-effects of inducing emesis. Studies have shown that PDE4 has 4 subtypes: PDE4A, 4B, 4C and 4D; wherein PDE4B relates to anti-inflammation, PDE4D also has anti-inflammatory function, but they also relate to central emesis reaction. Some studies have shown that Cilomilast has activity to PDE4D 10 time better than the activity of PDE4B, while Roflumilast has equivalent activity to PDE4B and PDE4D. Therefore, PDE4 inhibitors with equivalent activity to PDE4B and PDE4D would be designed to remarkably reduce side-effect of emesis, increase therapeutic window of drug, and achieve optimal therapeutic effects.
MK-0873 is a drug under study in Merck & Co., and has now entered into clinical phase II. This compound had a module different from Roflumilast and Cilomilast, and data in documents show that it has equivalent activity to various subtypes of PDE4, thereby reducing frequency of adverse effects such as emesis in some extent, increasing therapeutic window and fulfilling better therapeutic effects.



We further optimize the module of MK-0873 compound so as to find desired drug of PDE4 inhibitors to meet clinical requirements.